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Highlights • Risk factors for rhinovirus lower respiratory tract infection are not well characterized. • Several risk factors in hematopoietic cell transplant recipients were identified. • A risk score for progression to lower respiratory tract infection was developed., Human rhinovirus lower respiratory tract infection (LRTI) is associated with mortality after hematopoietic cell transplantation (HCT); however, risk factors for LRTI are not well characterized. We sought to develop a risk score for progression to LRTI from upper respiratory tract infection (URTI) in HCT recipients. Risk factors for LRTI within 90 days were analyzed using Cox regression among HCT recipients with rhinovirus URTI between January 2009 and March 2016. The final multivariable model included factors with a meaningful effect on the bootstrapped optimism corrected concordance statistic. Weighted score contributions based on hazard ratios were determined. Cumulative incidence curves estimated the probability of LRTI at various score cut-offs. Of 588 rhinovirus URTI events, 100 (17%) progressed to LRTI. In a final multivariable model allogeneic grafts, prior rhinovirus URTI, low lymphocyte count, low albumin, positive cytomegalovirus serostatus, recipient statin use, and steroid use ≥2 mg/kg/day were associated with progression to LRTI. A weighted risk score cut-off with the highest sensitivity and specificity was determined. Risk scores above this cut-off were associated with progression to LRTI (cumulative incidence 28% versus 11% below cut-off; P < .001). The weighted risk score for progression to rhinovirus LRTI can help identify and stratify patients for clinical management and for future clinical trials of therapeutics in HCT recipients.

Parainfluenza virus (PIV) infection can progress from upper respiratory tract infection (URTI) to lower respiratory tract disease (LRTD) in immunocompromised hosts. Risk factors for progression to LRTD and presentation with LRTD without prior URTI are poorly defined. Hematopoietic cell transplant (HCT) recipients with PIV infection were retrospectively analyzed using standardized definitions of LRTD. PIV was detected in 540 HCT recipients; 343 had URTI alone and 197 (36%) had LRTD (possible, 76; probable, 19; proven, 102). Among 476 patients with positive nasopharyngeal samples, the cumulative incidence of progression to probable/proven LRTD by day 40 was 12%, with a median time to progression of 7 days (range, 2 to 40). In multivariable analysis monocytopenia (hazard ratio, 2.22; P = .011), steroid use ≥1mg/kg prior to diagnosis (hazard ratio, 1.89; P = .018), co-pathogen detection in blood (hazard ratio, 3.21; P = .027), and PIV type 3 (hazard ratio, 3.57; P = .032) were associated with increased progression risk. In the absence of all 4 risk factors no patients progressed to LRTD, whereas progression risk increased to >30% if 3 or more risk factors were present. Viral load or ribavirin use appeared to have no effect on progression. Among 121 patients with probable/proven LRTD, 64 (53%) presented LRTD without prior URTI, and decreased lung function before infection and lower respiratory co-pathogens were risk factors for this presentation. Mortality was unaffected by the absence of prior URTI. We conclude that the risk of progression to probable/proven LRTD exceeded 30% with ≥3 risk factors. To detect all cases of LRTD, virologic testing of lower respiratory samples is required regardless of URTI symptoms.

INTRODUCTION: Recent data suggest human rhinovirus (HRV) is associated with lower respiratory tract infection and mortality in hematopoietic cell transplant (HCT) recipients. Examining risk factors for prolonged viral shedding may provide critical insight for the development of novel therapeutics and help inform infection prevention practices. Our objective was to identify risk factors for prolonged shedding of HRV post-HCT. MATERIALS AND METHODS: We prospectively collected weekly nasal samples from allogeneic HCT recipients from day 0 to day 100 post-transplant, and performed realtime RT-PCR (12/2005 to 2/2010). Subjects with symptomatic HRV infection and a negative test within 2 weeks of the last positive were included. Duration of shedding was defined as time between the first positive and first negative samples. Cycle threshold (Ct) values were used as a proxy for viral load. HRV species were identified by sequencing the 5’ non-coding region. Logistic regression analyses were performed to evaluate factors associated with prolonged shedding (≥21 days). RESULTS: We identified 38 HCT recipients with HRV infection fulfilling study criteria (32 adults, 6 children). Median duration of shedding was 9.5 days (2-89 days); 18 patients had prolonged shedding. Among 26 samples sequenced, 69% were species A, and species B and C accounted for 15% each; the median shedding duration of HRV did not differ between species (P = 0.17). Bivariable logistic regression analyses suggest that initial high viral load (low Ct value) is associated with prolonged shedding. CONCLUSIONS: HCT recipients with initial high viral loads are at risk for prolonged HRV viral shedding.

Introduction Recent animal and human data suggest that antibiotic exposure prior to respiratory viral infection (RVI) increases risk of respiratory disease progression, presumably due to immunomodulatory effects of changes in the microbiota. However, few studies have identified the specific antibiotics that may be linked to respiratory viral disease progression. Objectives To investigate the associations between antibiotic exposure and disease progression of select RVIs after allogeneic hematopoietic cell transplantation (HCT). Methods We analyzed patients who underwent allogeneic HCT (4/2008-9/2018) and had their first RVI due to parainfluenza virus (PIV), respiratory syncytial virus (RSV), human metapneumovirus (MPV) or human rhinovirus (HRV) during the first 100 days after HCT. Antibiotic exposure in the 21 days before RVI onset was defined as A) any versus no use of specific antibiotics, and B) total antibiotic-days. Antibiotic-days was defined as cumulative sum of antibiotics received during each day in the specified time window. The probability of disease progression was estimated by cumulative incidence curves, treating death as a competing risk. We used Cox proportional hazard models to examine associations between antibiotic exposure and risk of disease progression to LRTD, adjusting for type of RVI, age at transplant, steroid use, lymphopenia and neutropenia before RVI onset. Data were censored at death, discharge, or 30 days post-RVI onset, whichever came first. Results We identified 469 HCT recipients (379 adults, 90 children) with first RVI (PIV 93, RSV 54, MPV 27, HRV 295), of which, 124 progressed to LRTD. Cumulative incidence of LRTD by tertiles of the total antibiotic-days (median 11, range 0-56) during the 21 days before onset of RVI is shown in Figure 1. In separate models, higher total antibiotic-days, use of antibiotics with broad anaerobic activity and use of cephalosporins with limited anaerobic activity were significantly associated with progression to LRTD. Figure 2 shows a forest plot of the adjusted hazard ratios between type of antibiotic exposure and progression to LRTD. Conclusion This study suggests that cumulative exposure to antibiotics prior to RVI is a risk factor for respiratory viral disease progression. Despite complex antibiotic use patterns in HCT recipients, our findings also suggest antibiotics of varying spectra may be associated with respiratory viral disease progression.

Early detection of subclinical lung function decline may help identify allogeneic hematopoietic cell transplant (HCT) recipients who are at increased risk for late noninfectious pulmonary complications, including bronchiolitis obliterans syndrome. We evaluated the use of handheld spirometry in this population. Allogeneic HCT recipients enrolled in a single-center observational trial performed weekly spirometry with a handheld spirometer for 1 year after transplantation. Participants performed pulmonary function tests in an outpatient laboratory setting at 3 time points: before transplantation, at day 80 after transplantation, and at 1 year after transplantation. Correlation between the 2 methods was assessed by Pearson and Spearman correlations; agreement was assessed using Bland-Altman plots. A total of 437 subjects had evaluable pulmonary function tests. Correlation for forced expiratory volume in 1 second (FEV1) was r = .954 (P.0001) at day 80 and r = .931 (P.0001) at 1 year when the handheld and laboratory tests were performed within 1 day of each other. Correlation for handheld forced expiratory volume in 6 seconds (FEV6) with laboratory forced vital capacity was r = .914 (P.0001) at day 80 and r = .826 (P.0001) at 1 year. The bias, or the mean difference (handheld minus laboratory), for FEV1 at day 80 and 1 year was -.13 L (limits of agreement, -.63 to .37) and -.10 L (limits of agreement, -.77 to .56), respectively. FEV6 showed greater bias at day 80 (-.51 L [limits of agreement, -1.44 to .42]) and 1 year (-.40 L [limits of agreement, -1.81 to 1.01]). Handheld spirometry correlated well with laboratory spirometry after allogeneic HCT and may be useful for self-monitoring of patients for early identification of airflow obstruction.

Introduction Acute kidney injury (AKI) is common in hematopoietic cell transplant (HCT) recipients. Few studies have evaluated whether BK polyomavirus (BKV) infections are associated with kidney disease in the HCT population, and results have not been conclusive. Objectives Using retrospectively collected BK plasma viral loads from a large cohort of HCT recipients, we assessed the relationship between plasma BKV replication and AKI through an analysis of BK viral load kinetics, the occurrence of AKI, and change in serum creatinine. Methods Weekly BK viral loads were obtained during the first 100 days after HCT in 403 patients between 2007-2014 (Hill et al., Blood 2017). We defined AKI according to KDIGO (Kidney Disease Improving Global Outcomes) criteria and recovery from AKI as a reduction in serum creatinine to within ten percent of baseline, both sustained for 48 hours. Viral load kinetics of interest included peak viral load, area under the curve (AUC) and cross-sectional BK viral load (log10 BK viral load). Using these weekly longitudinal measures, we estimated the relationships between BKV kinetics and AKI using generalized linear models with robust variance estimates for the outcomes of 1) mean change in serum creatinine (from baseline) and 2) odds of AKI episodes, each adjusted for acute graft versus host disease, use of nephrotoxic medications (cidofovir, foscarnet), bilirubin, conditioning regimen, age, sex, and cell source. Results Fifty-four percent (218/402) of HCT recipients had detection of BKV in at least one sample, and twenty-eight percent (113/403) had at least one BK viral load ≥ 10,000 copies/mL in the first 100 days. Sixty-eight percent (275/403) had at least one AKI episode median onset by day 27 (range 1-98). Logistic regression models did not show significant associations for log10BK viral load, peak viral load and AUC with odds of subsequent AKI (Figure1). In the linear models, BK viral load kinetics were associated with small increases in mean serum creatinine (mg/dL) by 0.025 for each log10 increase (95% CI, 0.01-0.04; p Conclusion Increased plasma BK viral load was associated with small increases in serum creatinine after allogeneic HCT, but the clinical importance of these changes is low. We found no statistically significant association between plasma BKV detection and development of AKI.

Background The use of chimeric antigen receptor (CAR) T cell immunotherapy for refractory malignancy and other diagnoses is increasing rapidly. This approach has resulted in high response rates in children with refractory acute lymphoblastic leukemia (ALL). However many patients presenting for this therapy are at high risk for infections due to prior chemotherapy regimens and history of multiple relapses. Adding to the risk of infection is pre-infusion immunosuppressive lymphodepletion chemotherapy and post-therapy cytokine release syndrome (CRS) which often requires treatment with tocilizumab and steroids. In addition, CD19 CAR T cells may deplete normal CD19+ B cells, potentially resulting in low immunoglobulin G levels, further increasing the risk of infection. The infectious complications of this therapeutic approach have not been well studied in children. Methods We reviewed medical records of patients receiving CD 19+ CAR T cells for refractory ALL and non-Hodgkin's lymphoma through protocol PLAT 02 at Seattle Children's Hospital between 2014 and 2017. Pre-therapy infections, antimicrobial prophylaxis and development and treatment of CRS and neurotoxicity were noted. We assessed the timing, type and severity (1=no treatment, 2=oral treatment required, 3=intravenous therapy required, 4=life threatening, 5=fatal) of each incident infection. Primary outcomes were the incidence and type of infection in the 28 days post T- cell infusion. Mortality was a secondary outcome. Results 83 patients received CAR T-cell therapy during the study period. The median age was 12 years (range 1-25). All but three had ALL as an underlying diagnosis and 55% had preceding hematopoietic cell transplantation. More than half of participants (61%) had a new infection or were actively being treated for an infection in the 90 days prior to T cell infusion. 90% of patients developed CRS. 25 patients (30%) developed 32 episodes of infection in the first 28 days post CAR T cell infusion (Figure 1a). Bacterial infections were most common (n=20, 18%) consisting of 16 episodes of bacteremia (N = 6 gram negative bacteria and N = 10 gram positive bacteria), 2 clostridium difficile infections and 2 bacterial site infections (Figure 1b). 95% of bacterial infections were deemed grade 3 severity or higher. Ten participants (12%) had viral infections, of which 90% were caused by respiratory viruses (Figure 1c). One patient developed an incident invasive mold infection. Three patients died in the four weeks following therapy; none of these deaths were clearly infection related. Conclusions Infection occurs frequently in patients receiving CD19 targeted CAR T cell therapy for refractory ALL and NHL. Understanding the type and timing of infections and contributing risk factors could help inform prophylactic and monitoring strategies to improve outcomes in this patient population.

Introduction Bacterial superinfection following moderate to severe respiratory viral infections (RVIs), especially influenza (Flu), is well described in immunocompetent hosts. The clinical impact of preceding RVIs on the development of bacterial superinfection in hematopoietic cell transplant (HCT) recipients may be significant although data are limited. Furthermore, the impact of upper respiratory tract infection (URTI) on this outcome has not been systematically evaluated. Objectives To investigate whether URTI due to specific respiratory viruses was associated with increased risk of developing bacteremia or bacterial pneumonia post-HCT. Methods In a longitudinal surveillance study of RVIs among allogeneic HCT recipients conducted from 2005-10, weekly post-HCT nasal washes were collected through day 100. Nasal and bronchoalveolar lavage samples were tested by multiplex PCR for respiratory syncytial virus, parainfluenza viruses (PIV)1–4, Flu A/B, human metapneumovirus (HMPV), adenovirus, rhinoviruses and coronaviruses. URTI was defined as having respiratory virus detected from nasal samples with respiratory symptoms. Bacteremia and bacterial pneumonia were defined as growth of significant bacteria (e.g., Coagulase-negative staphylococci was defined as insignificant bacteria) from blood and lower respiratory tract samples including bronchoalveolar lavage, respectively. Separate Cox proportional hazards models were used to examine associations between first URTI for individual viruses and the subsequent development of first bacteremia and/or bacterial pneumonia by 100 days post-HCT. Results We identified 471 HCT recipients (median age: 51 years, range 8 months-75 years). Number of patients for each first outcome event by 100 days post-HCT included the following: Gram-positive bacteremia (n=64), Gram-negative bacteremia (n=53), Gram-positive pneumonia (n=46), Gram-negative pneumonia (n=8), and either bacteremia or pneumonia (n=152). After adjusting for pre-transplant factors only and pre- and post-transplant factors, significant URTI variables for outcomes in both models were (1) Flu A for gram-positive bacteremia, (2) HMPV for gram-positive pneumonia, and (3) HMPV for bacteremia or bacterial pneumonia (Figure). The association between PIV URTI and development of bacteremia or pneumonia approached statistical significance. Conclusion In HCT recipients, URTIs due to Flu A and HMPV are significant risk factors for the development of gram-positive bacteremia and pneumonia, respectively. Further studies are needed to assess whether prevention or early diagnostic and treatment strategies for RVIs can reduce the risk of bacterial infection.

Introduction Respiratory infections after HCT lead to significant morbidity, mortality, and health care costs due to pulmonary complications. In up to a third of patients following allogeneic HCT, infection can progress from an upper to a lower respiratory tract infection. Without vaccines or effective therapeutics for most viruses, very little can be done beyond supportive care. Objectives There is a need to identify risk factors for virus acquisition in HCT recipients in order to develop and implement better preventative interventions. Methods In a prospective study, 471 HCT patients enrolled between 2005 and 2010 underwent weekly PCR-based surveillance for RSV, metapneumovirus, parainfluenza virus 1-4, influenza A and B, rhinovirus, coronavirus, and adenovirus. Detailed weekly surveys were collected from subjects for up to 1 year post-transplant on symptoms and exposures to children under 10 years or sick contacts (within 3 feet for more than 1 hour total in the past week). We performed multivariable Cox regression analysis to identify risk factors associated with the time to first positive respiratory viral detection by PCR (asymptomatic and symptomatic) within the first 100 days HCT. Results In this cohort, 211 patients (45%) acquired a respiratory virus in the first 100 days after transplant. Of those infected, 88 (42%) were symptomatic with at least 2 respiratory symptoms. We found significantly higher risk of acquiring any respiratory viral infection for patients with underlying chronic leukemia compared with other hematologic malignancies [hazard ratio (HR) 1.79 (1.16 – 2.77)], exposure to children under or over 4 years [HR 1.84 (1.36 – 2.48)], exposure to contacts with cold symptoms [HR 1.47 (1.02 – 2.12)], exposure to systemic steroids [HR 1.49 (1.07 – 2.08)], and absolute monocyte counts < 100/µL [HR 1.81 (1.12 – 2.94)]. Age, age of child exposure, gender, smoking history, season, conditioning regimen, donor relationship, cell source, presence of acute GVHD, albumin level, total IgG level, lymphocyte counts, and neutrophil counts were not associated with risk for acquisition. We also analyzed the association of these same variables with the time to first positive respiratory viral detection with symptomatic respiratory disease. We found that exposure to children [HR 1.56 (1.03 – 2.35)] and exposure to steroids [HR 1.59 (1.01 – 2.52)] remained associated with acquisition of symptomatic respiratory viral infection. Conclusions These data support the contribution of both exposure and immunologic determinants to the risk of respiratory viral acquisition with and without development of symptoms. Although many infections were asymptomatic, patients receiving steroids and those in close proximity to children may benefit from closer monitoring and counseling in the early post-transplant period.

Human metapneumovirus (HMPV), a common respiratory virus, can cause severe disease in pre- and post-hematopoietic cell transplantation (HCT) recipients. We conducted a retrospective cohort analysis in HCT patients with HMPV (n = 23) or respiratory syncytial virus (n = 23) detected in bronchoalveolar lavage samples by reverse transcription PCR between 2006 and 2011 to determine disease characteristics and factors associated with outcome. Mortality rates at 100 days were 43% for both HMPV and respiratory syncytial virus lower respiratory tract disease. Steroid therapy, oxygen requirement >2 L or mechanical ventilation, and bone marrow as cell source were significant risk factors for overall and virus-related mortality in multivariable models, whereas the virus type was not. The presence of centrilobular/nodular radiographic infiltrates was a possible protective factor for mechanical ventilation. Thus, HMPV lower respiratory tract disease is associated with high mortality in HCT recipients. Earlier detection in combination with new antiviral therapy is needed to reduce mortality among HCT recipients.

Respiratory syncytial virus (RSV) infection is an important complication after hematopoietic cell transplantation (HCT), and RSV lower respiratory tract disease (LRD) results in substantial early mortality and late airflow obstruction among survivors. Factors associated with poor outcome are unknown. We evaluated the effect of transplant and treatment factors on overall survival, mortality from respiratory failure, and pulmonary function among 82 HCT recipients who had RSV LRD between 1990 and 2011. All patients received aerosolized ribavirin. In multivariable analyses, only the use of marrow or cord blood as graft source (adjusted hazard ratio [aHR], 4.1; 95% confidence interval [CI], 1.8 to 9.0; P

Viruses that cause acute respiratory illness in the general population and are responsible for hospitalizations in persons of all ages with underlying medical conditions are also a common cause of respiratory disease in transplant recipients. With the widespread availability of sensitive and reliable molecular detection methods, common respiratory viruses including respiratory syncytial virus (RSV), influenza and parainfluenza viruses (PIVs), adenoviruses, rhinoviruses (RhV), and coronaviruses have been detected worldwide in transplant recipients. More recently, newly identified viruses such as human metapneumoviruses (HMPV) (1,2), new strains of coronaviruses (3), and bocavirus have also been detected in symptomatic transplant recipients (4).

Infections due to community-acquired respiratory viruses are important causes of morbidity and mortality among immunocompromised patients. Respiratory syncytial virus, influenza viruses, and parainfluenza viruses are the most frequent causes of serious lower respiratory tract infections in this patient population. Early diagnosis, often possible with the use of rapid detection assays, is essential for optimal management and prevention of the spread of these serious infections to other vulnerable patients.Biol Blood Marrow Transplant 2001;7 Suppl:2S-4S.

The impact of cytokines induced during influenza infection has been described, but the effect of corticosteroids on clinical outcomes is unclear. Although antiviral therapy has been well studied in immunocompetent subjects, few data exist on its clinical efficacy in immunocompromised populations. Data from 143 hematopoietic cell transplant recipients with documented seasonal influenza infection were reviewed to examine the impact of different corticosteroid regimens and antiviral therapy on clinical outcomes. In multivariable analyses, there was no observed difference between patients who received no, low doses (

Hematopoietic cell transplantation is an effective treatment for patients with nonmalignant diseases and for many is the only known cure. Conventional myeloablative regimens have been associated with unacceptably high early transplant-related mortality (TRM), particularly in patients with comorbid conditions. This prospective multicenter trial was designed to determine the safety and engraftment efficacy of treosulfan-based conditioning in patients with nonmalignant diseases. Thirty-one patients received HLA-matched related (n = 4) or unrelated (n = 27) grafts after conditioning with treosulfan (total dose, 42 g/m2), fludarabine (total dose, 150 mg/m2), ± thymoglobulin (6 mg/kg; n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. All patients engrafted. Day-100 TRM was 0%. With a median follow-up of 2 years, the 2-year survival was 90%. Three patients died of GVHD, recurrent hemophagocytic lymphohistiocytosis, and a surgical complication, respectively. The cumulative incidences of grades II to IV and III to IV acute GVHD at day 100 and chronic GVHD at 2 years were 62%, 10%, and 21%, respectively. Patients who received thymoglobulin had a significantly lower incidence of grades III to IV acute GVHD (0% versus 33%; P = .005). These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with low toxicity and improved survival in patients with nonmalignant diseases and support the need for future disease-specific clinical trials.

s / Biol Blood Marrow Transplant 21 (2015) S266eS321 S318 (higher CT value), whereas the presence of an increased number of symptoms ( 3) was associated with a higher viral load. Lower viral load at initial surveillance testing correlated with an increased likelihood of being asymptomatic initially and remaining asymptomatic throughout the viral shedding episode. These results provide initial support for the use of viral load as a clinical endpoint in interventional trials.